Bacteremia can lead to septic shock and death in infected individuals, yet many aspects of bacteremia remain poorly understood in humans. In particular the host responses to bacterial components and the suppression of these responses by virulence factors in humans mononuclear cells has not been fully investigated and this has limited the development pf new therapeutics. Using Bacillus anthracis as a model system we are investigating inflammatory stimuli (peptidoglycan) and modulation of responses to this stimuli by anthrax toxin. In particular we are characterizing the induction of antimicrobials by PGN and studying how anthrax lethal toxin, but not edema toxin, suppresses this response. The first aim of this project is to characterize the BaPGN-induced antimicrobial response and its modulation by anthrax toxin in human PBMCs. The second aim is to characterize the differential mechanisms by which LT and ET modulate inflammatory and antimicrobial responses. The final aim is to examine the interplay between BaPGNinduced proinflammatory/antimicrobial factors and their suppression by anthrax toxin in an in vivo model. Completing these aims will address our overall goal of defining the molecular and cellular events occurring between a gram positive pathogen that causes bacteremia and the host responses to that pathogen.